Recent studies have provided evidence for the presence of a Ca2+ receptor on the surface of parathyroid cells which enables these cells to detect small changes in the concentration of extracellular Ca2+ and thereby alter parathyroid hormone secretion. This Ca2+ receptor is coupled to the mobilization of intracellular Ca2+ and shows many of the biochemical features common to more conventional Ca2+ mobilizing receptors. The only agents known to act at the Ca2+ receptor are di- and trivalent metal cations. The proposed studies examine the possibility that certain organic compounds might behave similarly to extracellular Ca2+ and regulate PTH secretion by acting as ligands at the Ca2+ receptor. Organic polycations (most notably spermine) will be examined for their ability using bovine and human parathyroid cells to: 1) mobilize intracellular Ca2+; 2) increase inositol phosphate formation; 3) decrease cyclic AMP formation; and 4) inhibit PTH secretion. Comparisons of these results will be made with those obtained with extracellular Ca2+ to determine if both organic and inorganic agents react through the same receptor-dependent mechanism. Organic compounds acting similarly to extracellular Ca2+ might then provide lead structures for the development of novel therapeutic agents effective in the treatment of various bone and mineral-related disorders such as hyperparathyroidism and osteoporosis.